Tag Archives: Hemp

Analysis of Toxicity Effects of Delta-9-Tetrahydrocannabinol on Isolated Rat Heart Mitochondria

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Publication Cover“Mitochondria have the main roles in myocardial tissue homeostasis, through providing ATP for the vital enzymes in intermediate metabolism, contractile apparatus and maintaining ion homeostasis. Mitochondria-related cardiotoxicity results from the exposure with illicit drugs have previously reported. These illicit drugs interference with processes of normal mitochondrial homeostasis and lead to mitochondrial dysfunction and mitochondrial-related oxidative stress.

Here, we investigated this hypothesis that delta-9-tetrahydrocannabinol (Delta-9-THC) as a main cannabinoid found in cannabis could directly cause mitochondrial dysfunction.

Our observation showed that THC did not cause a deleterious alteration in mitochondrial functions, ROS production, MMP collapse, mitochondrial swelling, oxidative stress and lipid peroxidation in used concentrations (5-100 µM), even in several tests, toxicity showed a decreasing trend.

Altogether, the results of the current study showed that THC is not directly toxic in isolated cardiac mitochondria, and even may be helpful in reducing mitochondrial toxicity.”

https://pubmed.ncbi.nlm.nih.gov/34431445/

https://www.tandfonline.com/doi/abs/10.1080/15376516.2021.1973168?journalCode=itxm20

Localisation of Cannabinoid and Cannabinoid-Related Receptors in the Horse Ileum

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Journal of Equine Veterinary Science“Colic is a common digestive disorder in horses and one of the most urgent problems in equine medicine. A growing body of literature has indicated that the activation of cannabinoid receptors could exert beneficial effects on gastrointestinal inflammation and visceral hypersensitivity.

The localisation of cannabinoid and cannabinoid-related receptors in the intestine of the horse has not yet been investigated. The purpose of this study was to immunohistochemically localise the cellular distribution of canonical and putative cannabinoid receptors in the ileum of healthy horses.

Distal ileum specimens were collected from six horses at the slaughterhouse. The tissues were fixed and processed to obtain cryosections which were used to investigate the immunoreactivity of canonical cannabinoid receptors 1 (CB1R) and 2 (CB2R), and three putative cannabinoid-related receptors: nuclear peroxisome proliferator-activated receptor-alpha (PPARα), transient receptor potential ankyrin 1 and serotonin 5-HT1a receptor (5-HT1aR).

Cannabinoid and cannabinoid-related receptors showed a wide distribution in the ileum of the horse.

The epithelial cells showed immunoreactivity for CB1R, CB2R and 5-HT1aR. Lamina propria inflammatory cells showed immunoreactivity for CB2R and 5-HT1aR. The enteric neurons showed immunoreactivity for CB1R, transient receptor potential ankyrin 1 and PPARα. The enteric glial cells showed immunoreactivity for CB1R and PPARα. The smooth muscle cells of the tunica muscularis and the blood vessels showed immunoreactivity for PPARα.

The present study represents a histological basis which could support additional studies regarding the distribution of cannabinoid receptors during gastrointestinal inflammatory diseases as well as studies assessing the effects of non-psychotic cannabis-derived molecules in horses for the management of intestinal diseases.”

https://pubmed.ncbi.nlm.nih.gov/34416995/

“Horses are often affected by gastrointestinal pathologies. Researchers are searching for new therapies for equine gastrointestinal diseases. New products with cannabinoid receptor agonists have been produced for horses. Cannabinoid receptors showed a wide distribution in the ileum of the horse. Activation of cannabinoids receptors could attenuate intestinal inflammation.”

https://www.sciencedirect.com/science/article/abs/pii/S073708062100318X?via%3Dihub

 

Pharmacological characterisation of the CB 1 receptor antagonist activity of cannabidiol in the rat vas deferens bioassay

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European Journal of Pharmacology“Cannabidiol is increasingly considered for treatment of a wide range of medical conditions. Binding studies suggest that cannabidiol binds to CB1 receptors. In the rat isolated vas deferens bioassay, a single electrical pulse causes a biphasic contraction from nerve-released ATP and noradrenaline. WIN 55,212-2 acts on prejunctional CB1 receptors to inhibit release of these transmitters. In this bioassay, we tested whether cannabidiol and SR141716 were acting as competitive antagonists of this receptor. Monophasic contractions mediated by ATP or noradrenaline in the presence of prazosin or NF449 (P2X1 inhibitor), respectively, were measured to a single electrical pulse delivered every 30 min. Following treatment with cannabidiol (10-100 μM) or SR141716 (0.003-10 μM), cumulative concentrations of WIN 55,212-2 (0.001-30 μM) were applied followed by a single electrical pulse. The WIN 55,212-2 concentration-contraction curve EC50 values were applied to global regression analysis to determine the pKB. The antagonist potency of cannabidiol at the CB1 receptor in the rat vas deferens bioassay matched the reported receptor binding affinity. Cannabidiol was a competitive antagonist of WIN 55,212-2 with pKB values of 5.90 when ATP was the effector transmitter and 5.29 when it was noradrenaline. Similarly, SR141716 was a competitive antagonist with pKB values of 8.39 for ATP and 7.67 for noradrenaline as the active transmitter. Cannabidiol’s low micromolar CB1 antagonist pKB values suggest that at clinical blood levels (1-3 μM) it may act as a CB1 antagonist at prejunctional neuronal sites with more potency when ATP is the effector than for noradrenaline.”

https://pubmed.ncbi.nlm.nih.gov/34416240/

https://www.sciencedirect.com/science/article/abs/pii/S0014299921005860?via%3Dihub

Cannabigerolic acid, a major biosynthetic precursor molecule in cannabis, exhibits divergent effects on seizures in mouse models of epilepsy

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British Journal of Pharmacology“Background and purpose: Cannabis has been used to treat epilepsy for millennia, with such use validated by regulatory approval of cannabidiol (CBD) for the treatment of Dravet syndrome. Unregulated artisanal cannabis-based products used to treat children with intractable epilepsies often contain relatively low doses of CBD but are enriched in other phytocannabinoids. This raises the possibility that other cannabis constituents might have anticonvulsant properties.

Experimental approach: We used the Scn1a+/- mouse model of Dravet syndrome to interrogate the cannabis plant for phytocannabinoids with anticonvulsant effects against hyperthermia-induced seizures. The most promising, cannabigerolic acid (CBGA), was further examined against spontaneous seizures and survival in Scn1a+/- mice. CBGA was also examined in conventional electroshock seizure models. In addition, we surveyed the pharmacological effects of CBGA across multiple drug targets.

Key results: The initial screen identified three phytocannabinoids with novel anticonvulsant properties: CBGA, cannabidivarinic acid (CBDVA) and cannabigerovarinic acid (CBGVA). CBGA was the most potent and potentiated the anticonvulsant effects of clobazam against hyperthermia-induced and spontaneous seizures, and was anticonvulsant in the MES threshold test. However, CBGA was proconvulsant in the 6-Hz threshold test and a high dose increased spontaneous seizure frequency in Scn1a+/- mice. CBGA was found to interact with numerous epilepsy-relevant targets including GPR55, TRPV1 channels and GABAA receptors.

Conclusion: These results suggest CBGA, CBDVA and CBGVA may contribute to the effects of cannabis-based products in childhood epilepsy. While these phytocannabinoids have anticonvulsant potential and could be lead compounds for drug development programs, several liabilities would need to be overcome before CBD is superseded by another in this class.”

https://pubmed.ncbi.nlm.nih.gov/34384142/

https://bpspubs.onlinelibrary.wiley.com/doi/10.1111/bph.15661

Add-on cannabidiol in patients with Dravet syndrome: Results of a long-term open-label extension trial

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“Objective: Add-on cannabidiol (CBD) reduced seizures associated with Dravet syndrome (DS) in two randomized, double-blind, placebo-controlled trials: GWPCARE1 Part B (NCT02091375) and GWPCARE2 (NCT02224703). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or GWPCARE2, were enrolled in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5.

Methods: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/ml), titrated from 2.5 to 20 mg/kg/day over a 2-week period, added to their existing medications. Based on response and tolerance, CBD could be reduced or increased to 30 mg/kg/day.

Results: Of the 330 patients who completed the original randomized trials, 315 (95%) enrolled in this open-label extension. Median treatment duration was 444 days (range = 18-1535), with a mean modal dose of 22 mg/kg/day; patients received a median of three concomitant antiseizure medications. Adverse events (AEs) occurred in 97% patients (mild, 23%; moderate, 50%; severe, 25%). Commonly reported AEs were diarrhea (43%), pyrexia (39%), decreased appetite (31%), and somnolence (28%). Twenty-eight (9%) patients discontinued due to AEs. Sixty-nine (22%) patients had liver transaminase elevations >3 × upper limit of normal; 84% were on concomitant valproic acid. In patients from GWPCARE1 Part B and GWPCARE2, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to Week 156 was 45%-74% for convulsive seizures and 49%-84% for total seizures. Across all visit windows, ≥83% patients/caregivers completing a Subject/Caregiver Global Impression of Change scale reported improvement in overall condition.

Significance: We show that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.”

https://pubmed.ncbi.nlm.nih.gov/34406656/

https://onlinelibrary.wiley.com/doi/10.1111/epi.17036

Efficacy and Safety of Cannabidiol Plus Standard Care vs Standard Care Alone for the Treatment of Emotional Exhaustion and Burnout Among Frontline Health Care Workers During the COVID-19 Pandemic: A Randomized Clinical Trial

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Free Download JAMA Network Logo Vector from Tukuz.Com“Importance: Frontline health care professionals who work with patients with COVID-19 have an increased incidence of burnout symptoms. Cannabidiol (CBD) has anxiolytic and antidepressant properties and may be capable of reducing emotional exhaustion and burnout symptoms.

Objective: To investigate the safety and efficacy of CBD therapy for the reduction of emotional exhaustion and burnout symptoms among frontline health care professionals working with patients with COVID-19.

Interventions: Cannabidiol, 300 mg (150 mg twice per day), plus standard care or standard care alone for 28 days.

Main outcomes and measures: The primary outcome was emotional exhaustion and burnout symptoms, which were assessed for 28 days using the emotional exhaustion subscale of the Brazilian version of the Maslach Burnout Inventory-Human Services Survey for Medical Personnel.

Results: A total of 120 participants were randomized to receive either CBD, 300 mg, plus standard care (treatment arm; n = 61) or standard care alone (control arm; n = 59) for 28 days. Of those, 118 participants (59 participants in each arm; 79 women [66.9%]; mean age, 33.6 years [95% CI, 32.3-34.9 years]) received the intervention and were included in the efficacy analysis. In the treatment arm, scores on the emotional exhaustion subscale of the Maslach Burnout Inventory significantly decreased at day 14 (mean difference, 4.14 points; 95% CI, 1.47-6.80 points; partial eta squared [ηp2] = 0.08), day 21 (mean difference, 4.34 points; 95% CI, 0.94-7.73 points; ηp2 = 0.05), and day 28 (mean difference, 4.01 points; 95% CI, 0.43-7.59 points; ηp2 = 0.04). However, 5 participants, all of whom were in the treatment group, experienced serious adverse events: 4 cases of elevated liver enzymes (1 critical and 3 mild, with the mild elevations reported at the final 28-day assessment) and 1 case of severe pharmacodermia. In 2 of those cases (1 with critical elevation of liver enzymes and 1 with severe pharmacodermia), CBD therapy was discontinued, and the participants had a full recovery.

Conclusions and relevance: In this study, CBD therapy reduced symptoms of burnout and emotional exhaustion among health care professionals working with patients during the COVID-19 pandemic. However, it is necessary to balance the benefits of CBD therapy with potential undesired or adverse effects. Future double-blind placebo-controlled clinical trials are needed to confirm the present findings.”

https://pubmed.ncbi.nlm.nih.gov/34387679/

“Daily administration of CBD, 300 mg, combined with standard care reduced the symptoms and diagnoses of anxiety, depression, and emotional exhaustion among frontline health care professionals working with patients with COVID-19. Cannabidiol may act as an effective agent for the reduction of burnout symptoms among a population with important mental health needs worldwide.”

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2782994

Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment

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ijms-logo“Cannabis sativa L. turned out to be a valuable source of chemical compounds of various structures, showing pharmacological activity. The most important groups of compounds include phytocannabinoids and terpenes.

The pharmacological activity of Cannabis (in epilepsy, sclerosis multiplex (SM), vomiting and nausea, pain, appetite loss, inflammatory bowel diseases (IBDs), Parkinson’s disease, Tourette’s syndrome, schizophrenia, glaucoma, and coronavirus disease 2019 (COVID-19)), which has been proven so far, results from the affinity of these compounds predominantly for the receptors of the endocannabinoid system (the cannabinoid receptor type 1 (CB1), type two (CB2), and the G protein-coupled receptor 55 (GPR55)) but, also, for peroxisome proliferator-activated receptor (PPAR), glycine receptors, serotonin receptors (5-HT), transient receptor potential channels (TRP), and GPR, opioid receptors.

The synergism of action of phytochemicals present in Cannabis sp. raw material is also expressed in their increased bioavailability and penetration through the blood-brain barrier. This review provides an overview of phytochemistry and pharmacology of compounds present in Cannabis extracts in the context of the current knowledge about their synergistic actions and the implications of clinical use in the treatment of selected diseases.”

https://pubmed.ncbi.nlm.nih.gov/33466734/

https://www.mdpi.com/1422-0067/22/2/778

Constituents of Cannabis Sativa

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“The Cannabis sativa plant has been used medicinally and recreationally for thousands of years, but recently only relatively some of its constituents have been identified.

There are more than 550 chemical compounds in cannabis, with more than 100 phytocannabinoids being identified, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

These phytocannabinoids work by binding to the cannabinoid receptors, as well as other receptor systems. Also within cannabis are the aromatic terpenes, more than 100 of which have been identified.

Cannabis and its constituents have been indicated as therapeutic compounds in numerous medical conditions, such as pain, anxiety, epilepsy, nausea and vomiting, and post-traumatic stress disorder.

This chapter provides an overview of some of the biological effects of a number of the cannabinoids and terpenes, as well as discussing their known mechanisms of action and evidence of potential therapeutic effects.”

https://pubmed.ncbi.nlm.nih.gov/33332000/

https://link.springer.com/chapter/10.1007%2F978-3-030-57369-0_1

Antiseizure effects of the cannabinoids in the amygdala-kindling model

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“Objective: Focal impaired awareness seizures (FIASs) are the most common seizure type in adults and are often refractory to medication. Management of FIASs is clinically challenging, and new interventions are needed for better seizure control. The amygdala-kindling model is a preclinical model of FIASs with secondary generalization.

The present study assessed the efficacy of cannabidiol (CBD), ∆9-tetrahydrocannabinol (THC), and a combination of CBD and THC in a 15:1 ratio at suppressing focal and secondarily generalized seizures in the amygdala-kindled rat.

Results: CBD alone produced a partial suppression of both generalized seizures (median effective dose [ED50 ] = 283 mg/kg) and focal seizures (ED40 = 320 mg/kg) at doses that did not produce ataxia. THC alone also produced partial suppression of generalized (ED50 = 10 mg/kg) and focal (ED50 = 30 mg/kg) seizures, but doses of 10 mg/kg and above produced hypolocomotion, although not ataxia. The addition of a low dose of THC to CBD (15:1) left-shifted the CBD dose-response curve, producing much lower ED50 s for both generalized (ED50 = 26 + 1.73 mg/kg) and focal (ED50 = 40 + 2.66 mg/kg) seizures. No ataxia or hypolocomotion was seen at these doses of the CBD + THC combination.

Significance: CBD and THC both have antiseizure properties in the amygdala-kindling model, although THC produces suppression of the amygdala focus only at doses that produce hypolocomotion. The addition of small amounts of THC greatly improves the effectiveness of CBD. A combination of CBD and THC might be useful for the management of FIASs.”

https://pubmed.ncbi.nlm.nih.gov/34251027/

https://onlinelibrary.wiley.com/doi/10.1111/epi.16973

Δ9-Tetrahydrocannabivarin (THCV): a commentary on potential therapeutic benefit for the management of obesity and diabetes

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figure1“Δ9-Tetrahydrocannabivarin (THCV) is a cannabis-derived compound with unique properties that set it apart from the more common cannabinoids, such as Δ9-tetrahydrocannabinol (THC). The main advantage of THCV over THC is the lack of psychoactive effects. In rodent studies, THCV decreases appetite, increases satiety, and up-regulates energy metabolism, making it a clinically useful remedy for weight loss and management of obesity and type 2 diabetic patients. The distinctions between THCV and THC in terms of glycemic control, glucose metabolism, and energy regulation have been demonstrated in previous studies. Also, the effect of THCV on dyslipidemia and glycemic control in type 2 diabetics showed reduced fasting plasma glucose concentration when compared to a placebo group. In contrast, THC is indicated in individuals with cachexia. However, the uniquely diverse properties of THCV provide neuroprotection, appetite suppression, glycemic control, and reduced side effects, etc.; therefore, making it a potential priority candidate for the development of clinically useful therapies in the future. Hopefully, THCV could provide an optional platform for the treatment of life-threatening diseases.”

https://pubmed.ncbi.nlm.nih.gov/33526143/

“The psychoactive effects of THC in marijuana are the main reasons for its classification as a Schedule I substance, even though it is the THC that the U.S. Food and Drug Administration (FDA) approved for appetite stimulation and weight gain. In contrast to THC, clinical and therapeutic advantages of THCV regarding its lack of psychoactive effects in human studies are of great value in pharmacotherapy. It is envisioned that the unique and diverse characteristics of THCV could be explored for further development into clinically useful medicines for the treatment of life-threatening diseases.”

https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-020-0016-7